Adverse Reactions in HCV-Infected Subjects without Cirrhosis or with Compensated Cirrhosis

The adverse reactions data for VOSEVI were derived from two Phase 3 clinical trials (POLARIS-1 and POLARIS-4) that evaluated a total of 445 subjects infected with genotype 1, 2, 3, 4, 5, or 6 HCV, without cirrhosis or with compensated cirrhosis (Child-Pugh A), who received VOSEVI for 12 weeks. VOSEVI was studied in placebo- and active-controlled (sofosbuvir/velpatasvir) trials [see Clinical Studies (14.1 and 14.2)].

The proportion of subjects who permanently discontinued treatment due to adverse events was 0.2% for subjects who received VOSEVI for 12 weeks.

The most common adverse reactions (adverse events assessed as causally related by the investigator and at least 10%) were headache, fatigue, diarrhea, and nausea in subjects treated with VOSEVI for 12 weeks.

Table 2 lists adverse reactions (adverse events assessed as causally related by the investigator, all grades) observed in at least 5% of subjects receiving 12 weeks of treatment with VOSEVI in the Phase 3 clinical trials. The side-by-side tabulation is to simplify presentation; direct comparison across trials should not be made due to differing trial designs.

In POLARIS-1, of the subjects receiving VOSEVI who experienced adverse reactions, 99% were mild or moderate (Grade 1 or 2) in severity. In POLARIS-4, of the subjects receiving VOSEVI who experienced adverse reactions, all the reported adverse reactions were mild or moderate (Grade 1 or 2) in severity.

Less Common Adverse Reactions Reported in Clinical Trials

The following adverse reactions occurred in less than 5% of subjects without cirrhosis or with compensated cirrhosis treated with VOSEVI for 12 weeks and are included because of a potential causal relationship.

Laboratory Abnormalities

Hepatobiliary Disorders

Hepatic decompensation, hepatic failure with NS3/4A protease inhibitor-containing regimens [see Warnings and Precautions (5.2)].

Cardiac Disorders

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with a sofosbuvir-containing regimen [see Warnings and Precautions (5.3) and Drug Interactions (7.3)].

Skin and Subcutaneous Tissue Disorders

Skin rashes, sometimes with blisters or angioedema-like swelling

Angioedema

Risk Summary

No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of VOSEVI (sofosbuvir, velpatasvir, or voxilaprevir) at exposures greater than those in humans at the recommended human dose (RHD) [see Data]. During organogenesis in the mouse, rat, and rabbit, systemic exposures (AUC) of velpatasvir were approximately 23 (mice), 4 (rats), and 0.5 (rabbits) times the exposure in humans at the RHD, while exposures of voxilaprevir were approximately 141 (rats) and 4 (rabbits) times the exposure in humans at the RHD. Exposures of the predominant circulating metabolite of sofosbuvir (GS-331007) were approximately 6 (rats) and 16 (rabbits) times the exposure in humans at the RHD. In rat pre/postnatal development studies, maternal systemic exposures (AUC) for each component of VOSEVI were approximately 7 (sofosbuvir metabolite GS-331007), 3 (velpatasvir), and 238 (voxilaprevir) times the exposure in humans at the RHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Risk Summary

It is not known whether the components of VOSEVI and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When the components of VOSEVI were administered to lactating rats, GS-331007 (the predominant circulating metabolite of sofosbuvir) and velpatasvir were detected in milk, while voxilaprevir was detected in the plasma of nursing pups likely due to the presence of voxilaprevir in milk. No significant effects of any of the drugs were observed in nursing rat pups [see Data].

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VOSEVI and any potential adverse effects on the breastfed child from VOSEVI or from the underlying maternal condition.

Data

Cardiac Electrophysiology

The effect of sofosbuvir 400 mg (recommended dosage) and 1200 mg (3 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.

The effect of velpatasvir 500 mg (5 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.

The effect of voxilaprevir 900 mg (9 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial. At a dose 9 times the recommended dose, voxilaprevir does not prolong QTc interval to any clinically relevant extent.

Specific Populations

Drug Interaction Studies

After oral administration of VOSEVI, sofosbuvir is rapidly absorbed and subject to extensive first-pass hepatic extraction (hydrolysis followed by sequential phosphorylation) to form the pharmacologically active triphosphate. In clinical pharmacology studies, both sofosbuvir and the primary circulating metabolite GS-331007 (dephosphorylated nucleotide metabolite) were monitored for purposes of pharmacokinetic analyses.

Sofosbuvir, velpatasvir, and voxilaprevir are substrates of drug transporters P-gp and BCRP while GS-331007 is not. Voxilaprevir, and to a lesser extent velpatasvir, are also substrates of OATP1B1 and OATP1B3. In vitro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 and of voxilaprevir by CYP1A2, CYP2C8, and primarily CYP3A4 was observed. Inducers of P-gp and/or moderate to strong inducers of CYP2B6, CYP2C8, or CYP3A4 (e.g., St. John's wort, carbamazepine) may significantly decrease plasma concentrations of sofosbuvir, velpatasvir, and/or voxilaprevir leading to reduced therapeutic effect of VOSEVI [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.3)]. Coadministration with drugs that inhibit P-gp and/or BCRP may increase sofosbuvir, velpatasvir, and/or voxilaprevir plasma concentrations without increasing GS-331007 plasma concentration. Coadministration with drugs that inhibit OATP may increase voxilaprevir plasma concentrations. Drugs that inhibit CYP2B6, CYP2C8, or CYP3A4 may increase plasma concentration of velpatasvir and/or voxilaprevir.

Sofosbuvir and GS-331007 are not inhibitors of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, or OCT1 and GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, or MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.

Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.

Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporters OCT1, renal transporters OCT2, OAT1, OAT3, or MATE1, or CYP or UGT1A1 enzymes.

The effects of coadministered drugs on the exposure of sofosbuvir, GS-331007, velpatasvir, and voxilaprevir are shown in Table 6. The effects of sofosbuvir, velpatasvir, voxilaprevir, sofosbuvir/velpatasvir, or VOSEVI on the exposure of coadministered drugs are shown in Table 7 [see Drug Interactions (7)].

No effect on the pharmacokinetic parameters of sofosbuvir, GS-331007, velpatasvir, or voxilaprevir was observed with the combination of emtricitabine, rilpivirine, and tenofovir alafenamide; famotidine; gemfibrozil; or the combination of raltegravir, emtricitabine, and tenofovir DF.

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with VOSEVI (ethinyl estradiol/norgestimate) or its components sofosbuvir/velpatasvir (dolutegravir) or sofosbuvir (methadone).

Mechanism of Action

Sofosbuvir is an inhibitor of the HCV NS5B RNA-dependent RNA polymerase, which is required for viral replication. Sofosbuvir is a nucleotide prodrug that undergoes intracellular metabolism to form the pharmacologically active uridine analog triphosphate (GS-461203), which can be incorporated into HCV RNA by the NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of the recombinant NS5B from HCV genotype 1b, 2a, 3a, and 4a with an IC50 value ranging from 0.36 to 3.3 µM. GS-461203 is neither an inhibitor of human DNA and RNA polymerases nor an inhibitor of mitochondrial RNA polymerase.

Velpatasvir is an inhibitor of the HCV NS5A protein, which is required for viral replication. Resistance selection in cell culture and cross-resistance studies indicate velpatasvir targets NS5A as its mode of action.

Voxilaprevir is a noncovalent, reversible inhibitor of the NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical inhibition assay, voxilaprevir inhibited the proteolytic activity of recombinant NS3/4A enzymes from clinical isolates of HCV genotypes 1b and 3a with Ki values of 38 and 66 pM, respectively.

Antiviral Activity

In HCV replicon assays, sofosbuvir had median EC50 values of 15–110 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 5a, and 6a. Velpatasvir had median EC50 values of 0.002–0.13 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, and 6e. Voxilaprevir had median EC50 values of 0.2–6.6 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a, 1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, 6e, and 6n.

Evaluation of sofosbuvir in combination with velpatasvir or voxilaprevir, as well as the combination of velpatasvir and voxilaprevir, showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

Persistence of Resistance-Associated Substitutions

No data are available on the persistence of sofosbuvir, velpatasvir, or voxilaprevir resistance-associated substitutions. NS5A inhibitor resistance-associated substitutions observed with administration of other NS5A inhibitors have been found to persist for longer than 1 year in most patients. The long-term clinical impact of the emergence or persistence of virus containing sofosbuvir, velpatasvir, or voxilaprevir resistance-associated substitutions is unknown.

Effect of Baseline HCV Variants on Treatment Response

Analyses were conducted to explore the association between SVR12 rates and preexisting baseline NS3/4A protease inhibitor and NS5A inhibitor resistance-associated substitutions for subjects in POLARIS-1 and POLARIS-4. Amino acid positions considered in resistance analyses included NS3 positions 36, 41, 43, 54, 55, 56, 155, 156, and 168, and NS5A positions 24, 28, 30, 31, 58, 92, or 93. Baseline resistance-associated amino acid substitutions, which may include natural polymorphisms or prior treatment-emergent substitutions relative to subtype-specific references, were identified by next generation sequencing analysis using a sensitivity threshold of 15% of the viral population.

Overall, the presence of baseline NS3/4A protease inhibitor, NS5A inhibitor, and nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions did not alter the SVR rates for DAA-experienced subjects in the POLARIS-1 and POLARIS-4 trials who received 12 weeks of VOSEVI. For subjects treated with VOSEVI for 12 weeks, SVR12 rates in subjects with or without baseline NS3 and NS5A resistance-associated substitutions in the POLARIS-1 and POLARIS-4 trials were all greater than or equal to 97%.

In POLARIS 1, which included NS5A inhibitor-experienced subjects, 79% (206/260) of subjects had baseline NS5A resistance-associated substitutions across all genotypes. The most prevalent NS5A resistance-associated substitutions were at primary resistance-associated amino acid positions 30 (97/206; 47%), 31 (58/206; 28%), and 93 (103/206; 50%). Fifty-five percent (n=113/206) of the subjects had a single NS5A resistance-associated substitution, while 2 resistance-associated substitutions were detected in 65/206 subjects (32%) and 3 or more were detected in 28/206 subjects (14%). Overall prevalence of NS3/4A protease inhibitor resistance-associated substitutions across all genotypes was 15% (37/248). The most prevalent NS3 resistance-associated substitutions were at positions 36 (5/17; 29%) and 168 (7/17; 41%) in genotype 1a and position 56 in genotype 1b (8/12; 67%). Substitutions at positions 36, 56, or 168 were detected in 1-2 subjects for each genotype 2, 3, or 4.

In POLARIS-4, which included DAA-experienced subjects who had not received an NS5A inhibitor, 32% (57/177) of subjects who received 12 weeks of VOSEVI had baseline NS5A inhibitor resistance-associated substitutions. Most of the subjects had a single NS5A resistance-associated substitution (n=40; 70%). The most prevalent NS5A resistance-associated substitution was at amino acid position 31 (n=27; 47%). Overall prevalence of baseline NS3/4A protease inhibitor resistance-associated substitutions was 12% (21/169). The most prevalent NS3 resistance-associated substitutions were at positions 55 (5/10) and 168 (3/10) in genotype 1a, position 56 in genotype 1b (3/5) and genotype 2 (3/3), and at position 168 in genotype 4 (3/3).

SVR12 was achieved in 18 of 19 (95%) subjects who had baseline nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions in POLARIS-1, including 2 subjects who had virus with the S282T nucleotide analog NS5B polymerase inhibitor resistance-associated substitution in addition to NS5A resistance-associated substitutions at baseline. In POLARIS-4, a total of 14 subjects had virus with nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions at baseline and all achieved SVR12.

Cross Resistance

Cross-resistance is possible between HCV NS3/4A protease inhibitors and between HCV NS5A inhibitors by class. Sofosbuvir, velpatasvir, and voxilaprevir were each active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions (e.g., voxilaprevir was fully active against virus with NS5A resistance-associated substitutions and nucleotide analog NS5B inhibitor resistance-associated substitutions).

Carcinogenesis and Mutagenesis

Impairment of Fertility

NS5A Inhibitor-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis (POLARIS-1)

POLARIS-1 was a randomized, double-blind, placebo-controlled trial that evaluated 12 weeks of treatment with VOSEVI compared with 12 weeks of placebo in DAA-experienced subjects with genotype 1, 2, 3, 4, 5, or 6 HCV infection without cirrhosis or with compensated cirrhosis who previously failed a regimen containing an NS5A inhibitor. Subjects with genotype 1 HCV infection were randomized 1:1 to each group. Subjects with genotype 2, 3, 4, 5, or 6 HCV infection were enrolled to the VOSEVI group. Randomization was stratified by the presence or absence of cirrhosis.

Demographics and baseline characteristics were generally balanced across treatment groups. Of the 415 treated subjects, the median age was 59 years (range: 27 to 84); 77% of the subjects were male; 81% were White; 14% were Black; 6% were Hispanic or Latino; 33% had a baseline body mass index at least 30 kg/m2; the majority of subjects had genotype 1 (72%) or genotype 3 (19%) HCV infection; 82% had a non-CC IL28B genotype (CT or TT); 74% had baseline HCV RNA levels at least 800,000 IU/mL; and 41% had compensated cirrhosis. In the POLARIS-1 trial, prior DAA regimens contained the following NS5A inhibitors: ledipasvir (51%), daclatasvir (27%), ombitasvir (11%), velpatasvir (7%), and elbasvir (3%).

Table 9 presents the SVR12 by HCV genotype for the POLARIS-1 trial. No subjects in the placebo group achieved SVR12.

DAA-Experienced Adults Without Cirrhosis or With Compensated Cirrhosis Who Had Not Received An NS5A Inhibitor (POLARIS-4)

POLARIS-4 was a randomized, open-label trial that evaluated 12 weeks of treatment with VOSEVI and 12 weeks of treatment with SOF/VEL in subjects with genotype 1, 2, 3, or 4 HCV infection without cirrhosis or with compensated cirrhosis who had previously failed a HCV DAA-containing regimen that did not include an NS5A inhibitor. Subjects whose only DAA exposure was an NS3/4A protease inhibitor were excluded. Subjects with genotype 1, 2, or 3 HCV infection were randomized 1:1 to each group. Randomization was stratified by HCV genotype and by the presence or absence of cirrhosis. Subjects with genotype 4 HCV infection were enrolled to the VOSEVI group. No subjects with genotype 5 or 6 were enrolled.

Demographics and baseline characteristics were generally balanced across treatment groups. Of the 333 treated subjects, the median age was 58 years (range: 24 to 85); 77% of the subjects were male; 87% were White, 9% were Black; 8% were Hispanic or Latino; 35% had a baseline body mass index at least 30 kg/m2; 81% had non-CC IL28B genotypes (CT or TT); 75% had baseline HCV RNA levels at least 800,000 IU/mL; and 46% had compensated cirrhosis. In the POLARIS-4 trial, prior DAA regimens contained sofosbuvir (85%) with the following: peginterferon alfa and ribavirin or ribavirin (69%), HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir; 15%), and investigational DAA (<1%). Of the 15% of subjects without prior sofosbuvir exposure, most received investigational HCV DAAs or approved HCV NS3/4A protease inhibitors, with or without peginterferon alfa and ribavirin.

Treatment with VOSEVI for 12 weeks resulted in numerically higher SVR12 rates than treatment with sofosbuvir/velpatasvir for 12 weeks in subjects with HCV genotype 1a and 3 infection. Comparable SVR12 rates were observed in subjects with HCV genotype 1b and 2 infection treated with VOSEVI for 12 weeks or with sofosbuvir/velpatasvir for 12 weeks. No comparison data are available for HCV genotypes 4, 5, and 6. Given these data, the additional benefit of VOSEVI has not been shown over sofosbuvir/velpatasvir for these genotypes and VOSEVI is only indicated for the treatment of HCV genotypes 1a or 3 infection in adults who previously received sofosbuvir without an NS5A inhibitor.

Table 10 presents the comparative virologic outcome data for HCV genotype 1, 2, and 3 subjects with prior exposure to a sofosbuvir-containing regimen.

In POLARIS-4, VOSEVI was administered for 12 weeks to 18 HCV genotype 4 subjects (with or without cirrhosis) who had prior exposure to a SOF-containing regimen without an NS5A inhibitor. All subjects achieved SVR12.